Population-based pharmacogenomic assessment of QT prolongation

基于人群的 QT 延长药物基因组学评估

• 批准号: 9925250
• 负责人: Carlos Iribarren
• 金额: $ 75.46万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925250
• 关键词: 6-Mercaptopurine; Address; Adult; African American; Aging; Alternative Therapies; American; Antibiotics; Antidepressive Agents; Antifungal Agents; Asians; Biological; CYP2C19 gene; California; Candidate Disease Gene; Carbamazepine; Cardiac; Cardiotoxicity; Cardiovascular system; Caucasians; Clinic; Collaborations; Complement; Cross-Sectional Studies; Data; Databases; Drug Interactions; Electrocardiogram; Environment; Equation; Ethnic group; European; Exposure to; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genotype; Goals; HLA-B Antigens; Health; Heart; Heterogeneity; Individual; Inpatients; Investigation; Ion Channel; Label; Latino; Light; Link; Literature; Measures; Mediating; Mediation; Meta-Analysis; Minority Groups; Modeling; Names; Outcome; Outpatients; Pacific Island Americans; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacology; Pharmacy facility; Phenotype; Physicians; Population; Population Heterogeneity; Predisposition; Quantitative Trait Loci; Research; Research Personnel; Risk; Sampling; Structure; Sudden Death; TPMT gene; Testing; Therapeutic; Time Study; Tissues; Torsades de Pointes; Translating; United Kingdom; Variant; Ventricular Arrhythmia; Work; abacavir; adjudicate; adverse drug reaction; adverse event risk; adverse outcome; biobank; bioinformatics tool; clinically relevant; clinically significant; clopidogrel; cohort; data resource; design; drug metabolism; drug withdrawal; epidemiology study; ethnic diversity; genetic epidemiology; genetic predictors; genetic testing; genetic variant; genome wide association study; genome-wide; genomic locus; health plan; heart rhythm; longitudinal analysis; member; novel; population based; prevent; programs; side effect

Abstract Cardiotoxicity of commonly prescribed medications, typically assessed by electrocardiographic features such as prolongation of the QT interval, is a relevant clinical topic because it has regulatory consequences (labelling and withdrawal of drugs) and is associated with potentially fatal patient-level outcomes (ventricular arrhythmias and Torsade de Pointes). We propose here to leverage the extensive phenotypic and genotypic data resources of the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment and Health (RPGEH), and the ability to link these data to other health plan databases, namely our pharmacy, electrocardiogram (ECG) and outpatient/inpatient utilization databases. In particular, we will use the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort members (n=110,266; n=69,276 with 1 or more available ECGs; 52,667 with two or more ECGs). Our ability to conduct longitudinal analyses of the QT interval over up to 20 years in a large and ethnically diverse population (The GERA cohort is 78% Caucasian, 6% Asian/Pacific Islander, 6% Latino, 3% African-American, 5% other or mixed) and to identify and characterize genetic loci that influence adverse drug reactions is unique and will advance our understanding of the genetic basis of cardiac toxicity of commonly prescribed medications. Replication of findings in Europeans will be sought in 70,944 Caucasian subjects with ECG, genome-wide and medication data in the UK Biobank. We will perform functional annotation of replicated hits to shed light on biological pathways and tissues involved. In addition, to complement this approach and to more fully address the downstream clinical significance of QT prolongation, we will also examine: a) genetic predictors of incident ventricular arrhythmias and of Torsade de Pointes; b) whether the identified gene by drug interactions are associated with these adverse outcomes and c) degree of mediation by QTc prolongation. Our results will be shared with the Pharmacogenomics Research Network (PGRN) for replication and meta-analytical purposes. Our long-term goal is to advance the field of the genetic basis of drug cardiotoxicity and its downstream consequences that will inform therapeutic considerations.

摘要 通常通过心电图特征（如 作为QT间期延长，是一个相关的临床主题，因为它具有监管后果（标签 和停药），并与潜在的致命性患者水平的结果（室性心律失常 和尖端扭转型室性心动过速）。我们建议利用广泛的表型和基因型数据资源 凯泽永久北方加州（KPNC）基因，环境和健康研究计划 （RPGEH），并能够将这些数据链接到其他健康计划数据库，即我们的药房， 心电图（ECG）和门诊/住院使用数据库。特别是，我们将使用遗传 成人健康和老龄化流行病学研究（GERA）队列成员（n= 110，266; n= 69，276，1或 更多可用ECG; 52，667例有两个或更多ECG）。我们对QT进行纵向分析的能力 间隔长达20年的大型和种族多样化的人群（GERA队列是78%的白人， 6%亚洲/太平洋岛民，6%拉丁美洲人，3%非洲裔美国人，5%其他或混合），并确定和 描述影响药物不良反应的遗传位点是独特的，将促进我们对药物不良反应的理解。 常见处方药心脏毒性的遗传基础。在欧洲人中复制研究结果 将在英国生物库中的70，944名具有ECG、全基因组和药物数据的高加索受试者中进行研究。 我们将对复制的命中进行功能注释，以阐明生物途径和组织 涉案此外，为了补充这种方法并更全面地解决下游临床问题， QT间期延长的意义，我们还将研究：a）发生室性心律失常的遗传预测因子 和尖端扭转型室性心动过速; B）通过药物相互作用鉴定的基因是否与这些相关 不良结局和c）QTc延长的介导程度。我们的成果将与 药物基因组学研究网络（PGRN），用于复制和荟萃分析目的。我们的长期 目标是推进药物心脏毒性及其下游遗传基础领域的研究。 这些结果将为治疗考虑提供信息。